Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer
Mark P. Labrecque, … , Peter S. Nelson, Colm Morrissey
Mark P. Labrecque, … , Peter S. Nelson, Colm Morrissey
Published October 1, 2019; First published July 30, 2019
Citation Information: J Clin Invest. 2019;129(10):4492-4505. https://doi.org/10.1172/JCI128212.
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Research Article Cell biology Oncology

Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole-genome RNA sequencing, gene set enrichment analysis, and immunohistochemistry. Our analyses revealed 5 mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: AR-high tumors (ARPC), AR-low tumors (ARLPC), amphicrine tumors composed of cells coexpressing AR and NE genes (AMPC), double-negative tumors (i.e., AR–/NE–; DNPC), and tumors with small cell or NE gene expression without AR activity (SCNPC). RE1 silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the 5 mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.

Authors

Mark P. Labrecque, Ilsa M. Coleman, Lisha G. Brown, Lawrence D. True, Lori Kollath, Bryce Lakely, Holly M. Nguyen, Yu C. Yang, Rui M. Gil da Costa, Arja Kaipainen, Roger Coleman, Celestia S. Higano, Evan Y. Yu, Heather H. Cheng, Elahe A. Mostaghel, Bruce Montgomery, Michael T. Schweizer, Andrew C. Hsieh, Daniel W. Lin, Eva Corey, Peter S. Nelson, Colm Morrissey

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Figure 1

Molecular profiling of mCRPC reveals a heterogeneous disease.

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Molecular profiling of mCRPC reveals a heterogeneous disease. (A) IHC of...
(A) IHC of 5 mCRPC sites from patients using antibodies to AR, PSA, CHGA, and SYP. Scale bars: 20 μM. (B) RNA-Seq heatmap of mCRPC specimens acquired through rapid autopsy from 2003–2017 (n = 98). REST-repressed NE genes are listed in the NEURO I panel (top), NE transcription factors are listed in the NEURO II panel (middle), and AR-associated genes are listed in the AR panel (bottom). Results are expressed as log2 fragments per kilobase of transcript per million mapped reads (FPKM) and colored according to scale. (C) Venn diagram showing the number of unique and shared upregulated genes between phenotypes relative to ARPC (up >3-fold; P < 0.05). ARPC (AR-high prostate cancer; AR+/NE–), ARLPC (AR-low prostate cancer; ARlow/NE–), AMPC (amphicrine prostate cancer; AR+/NE+), DNPC (double-negative prostate cancer; AR–/NE–), and SCNPC (small cell or neuroendocrine prostate cancer; AR–/NE+).